The possible causal relationship between hyperglycemia and diabetic microangiopathy is one of the most pressing problems in internal medicine. To test the hypothesis that they are causally related we have initiated a prospective, controlled, stratified and randomized clinical trial. This trial studies an inception cohort (diabetic nephropathy at stage zero) of Caucasian, type I diabetic kidney recipient patients. The main endpoint is glomerular mesangial expansion measured by electron microscopy at 2 and 5 yrs; this lesion seems causally related to dia-betic nephropathy. Arteriolar hyalinosis, glomerular basement membrane width (GBM) and renal immunohistochemistry are also studied. We have invited to participate in the study, thus far, more than 300 diabetics and 200 nondiabetic patients. Nineteen patients have been randomized to the standard treatment grp and 41 to the maximized treatment grp (3 to 4 insulin injections or insulin pumps). Attrition has resulted in 7 dropouts in the standard grp (3 deaths, 2 rejections, 2 uncompliant) and 10 in the maximized grp (4 deaths and 6 uncompliant). We have succeeded in maintaining clearly better metabolic control in the maximized grp. The histologic results from 2 yr follow up biopsies are promising, showing trends in favor of the maximized grp. There is already a stastically significant (borderline) difference favoring the maximized control grps for GBM width. We propose here to extend this trial for 5 more yrs, in order to perform enough kidney biopsies to effectively compare the two grps at 5 yrs for the crucial endpoint, morphometrically measured expansion of the mesangium. Recruitment of new patients for two more yrs is also proposed in order to increase the number of biopsies at 2 yrs; this may result in a significant difference between the two grps at two yrs and therefore earlier termination of the trial. It also gives us the option of continuing the study beyond the next 5 yr period to increase the number of 5 yr biopsies.